Small cerebral blood vessels are vitally important in controlling cerebral blood flow (CBF) and pressure within the brain. Minutes of inadequate blood supply results in neuronal death and thus, a dynamic regulation of CBF is critical. 20% of adults aged over 70 suffer from disruptions to the cerebral circulation; known as cerebral small vessel disease (cSVD). Over time, disturbances to cerebral small vessel function can result in strokes or dementia. In both of the most prevalent subtypes of dementia, Alzheimer's disease (AD) and vascular dementia (VaD), patients have a reduction in CBF. This has been noted in both clinical studies and animal models of disease, however the mechanisms behind this attenuated CBF is unknown. Hence, the aim of this study was to understand the mechanism behind reduced CBF in dementia. Through use of pressure myography, cerebral pial arteries in both an AD model (the APP23 mouse model) and a model of VaD (the spontaneously hypertensive, BPH/2 model) were significantly hyper-contracted compared to their controls. Arterial diameter is determined by a balancing influences of different vascular ion chanenls. As potanssium channels form a powerful vasodilatory influence over vascular smooth muscle cells (VSMC), and thus mediate dilation, a full characterisation of VSMC potassium channels was undertaken using pressure myography and patch clamp electrophysiology. In the APP23 mouse model of AD, impairments in cerebral pial endothelial, inward rectifying potassium channel function were discovered. This would contribute to deficiencies in neurovascular coupling that have also been described in AD patients. However, this was not seen in the hypertensive model of VaD. Common to both dementia models is the novel finding that the large-conductance calcium activated potassium (BK) channel is compromised. Upon investigation, in the APP23 mouse model, this BK channel defect was due to a reduction in calcium sparks, which activate the BK channel. However, in the hypertensive model of VaD, calcium sparks were preserved. Through cell staining and proximity ligation assay we found that in hypertension, the BK channel defect was due to separation of the VSMC and sarcoplasmic reticulum membranes results in in uncoupling of the BK and ryanadine receptors. Separation of the membranes results in inactivity of the BK channel and hyper-contractility of the blood vessels. In conclusion, BK channel deficiency is a common mechanism behind vascular dysfunction in two different subtypes of dementia, however the mechanisms behind the BK channel defect is unique to each model. This provides novel therapeutic targets for the treatment of cSVD, which may inhibit the progression in to dementia.
- Vascular Physiology
- Dementia
Potassium channel dysfunction in the development of small vessel disease of the brain
Taylor, J. (Author). 1 Aug 2023
Student thesis: Phd